We are studying gamma/delta T cell antigen receptors (TCR) and lymphocyte co-receptors with the purpose of understanding their role in the activation of an immune response. Our goal is to analyze these proteins biochemically and structurally. To do so requires that we produce sufficient amounts of protein for study and that we characterize the recombinant proteins for their appropriate functionality. Further study of their binding to ligands and of their three-dimensional structure by X-ray crystallography should lead to insights as to how these proteins function in the immune system. Unlike alpha/beta T cell receptors, which recognize peptide antigens bound to major histocompatibility complex molecules, gamma/delta TCRs can directly recognize antigens as intact proteins or non-peptidic compounds. About 5% of all primate peripheral blood T cells bear gamma/delta TCRs, most of which recognize non-peptidic phosphorylated antigens. In earlier work, we have determined the structure of a human gamma/delta TCR isolated from a T cell clone that is activated by phosphoantigens. We are now studying the binding of non-peptidic phosphorylated antigens to the gamma/delta TCR using crystallographic, biochemical, and biophysical techniques. We are also studying the structure and function of several lymphocyte co-receptors.